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Neuroimmunology for idiots. Part 2: Immune system in learning & memory – inflammatory cytokines.



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The last post discussed the role of T cells and T cell-derived IL-4, an anti-inflammatory cytokine. This post will focus on other inflammatory cytokines, in particular IL-1, IL-6 and TNF-α.  First, IL-1. Well the story is broadly pretty similar to that of T cell-derived IL-4: Take a normal mouse out of its home, put it in a different home, let’s say George’s Place, give it a noxious shock and then put it back home again. The mouse learns that George’s Place is not a good place to be, so that when the mouse is put in George’s Place, it freezes – ‘no movement except for respiration’ is the official definition. The duration of the freeze is the measure taken to reflect the strength of the association (I know – it seems like a measure that is not completely undodgy doesn’t it?) This is one of the most common animal studies in behavioural neuroscience – the contextual fear conditioning paradigm. Anyway, put a normal mouse through this and their IL-1 gene expression is elevated a day later.  Shock the mouse in its home cage and IL-1 gene expression is not affected – ie it is not the shock that has the effect but learning that the shock only occurs at George’s Place[1]. So, learning, at least in a fear paradigm, increases IL-1 manufacture and IL-1 is a pro-inflammatory cytokine, so, it seems, that learning in a fear paradigm induces an inflammatory-like process, at least in the hippocampus.

IL-1 can also facilitate learning. Give a mouse a shot of IL-1 immediately after a learning task[2], or immediately before it[3], and it has better memory of the task a week later. It is not just about fear either, giving a mouse IL-1 just before it does a water maze improves its performance on that too and if you block IL-1 signalling, or breed a mouse that can’t make IL-1, spatial memory is impaired[3].  Critically, all of the data on IL-1 involves spatial memory tasks, which are thought to rely on hippocampus function – very similar tasks that do not rely on hippocampus are unaffected by dosing up on IL-1, nor by knocking out the gene that signals IL-1.  The hippocampus is known to be important in spatial navigation – London cabbies have big hippocampii and the longer they have been cabbies the bigger it is![4]  Anyway, IL-1 manufacture seems to increase spatial learning and memory.

Interleukin-6, or IL-6, can be anti-inflammatory or pro-inflammatory. It is perhaps not surprising then, that this swinging voter can enhance or impair cognitive function.  Low and behold, there is actually a relevant human study looking at IL-6 administration to people with chronic fatigue syndrome who performed a range of cognitive tests[5].  Nothing happened. However, other studies measured IL-6 levels in plasma taken from patients with Lupus[6] or post surgery[7] and found that the higher the IL-6 count, the better the cognitive retention. So, more IL-6 production seems to be associated with improved memory.  By the way, TNF-α probably does too[8]. Is this necessarily good though? I will speculate more on that next post, but, to float it out there, there are some neural networks very active during and after surgery that we do not want to facilitate.

Finally, for today, prostaglandins, surprise surprise, enhance spatial learning. Prostaglandins are mainly made via rather famous enzymes called COX-1 and COX-2, which are expressed in neurones, glia and endothelial cells[8].  The COX brothers are defined according to where they have their effects – COX-1 is responsible for maintenance and protection of the gastrointestinal tract and COX-2 is, for us, more famous – contributes to inflammation and pain. COX-2 inhibitors impair memory and performance on spatial tasks, although, intriguingly, mice with genetically impaired COX-2 expression are just as good as their mates at learning to freeze at George’s[8].  That one might actually have a clinical implication because, as we know, there are a whole heap of people taking ibuprofen – you may very will be one of them. Do you feel as smart as you were before you started taking them? Actually, there is no evidence I can find that COX-2 inhibitors actually impair spatial memory in humans – perhaps it is time for a study….

But wait! All these situations are good and well – disrupt the brain and IL-1, IL-6, TNF-α and prostaglandins disrupt hippocampus-led spatial tasks.  However, in a homeostatically balanced brain, you can throw most of this out – IL-6, TNF-α and prostaglandins can all have the opposite effect. Jeepers. If anyone needed convincing that we are indeed fearfully and wonderfully complex, try to get a handle on the immune system without becoming convinced!

About Lorimer Moseley

Lorimer is NHMRC Senior Research Fellow with twenty years clinical experience working with people in pain. After spending some time as a Nuffield Medical Research Fellow at Oxford University he returned to Australia in 2009 to take up an NHMRC Senior Research Fellowship at Neuroscience Research Australia (NeuRA). In 2011, he was appointed Professor of Clinical Neurosciences & the Inaugural Chair in Physiotherapy at the University of South Australia, Adelaide. He runs the Body in Mind research groups. He is the only Clinical Scientist to have knocked over a water tank tower in Outback Australia.


[1] Goshen, I., Kreisel, T., Ounallah-Saad, H., Renbaum, P., Zalzstein, Y., Ben-Hur, T., Levy-Lahad, E., & Yirmiya, R. (2007). A dual role for interleukin-1 in hippocampal-dependent memory processes Psychoneuroendocrinology, 32 (8-10), 1106-1115 DOI: 10.1016/j.psyneuen.2007.09.004

[2] Yirmiya, R. (2002). Brain Interleukin-1 Is Involved in Spatial Memory and Passive Avoidance Conditioning Neurobiology of Learning and Memory, 78 (2), 379-389 DOI: 10.1006/nlme.2002.4072

[3] Song C, Phillips AG, & Leonard B (2003). Interleukin 1 beta enhances conditioned fear memory in rats: possible involvement of glucocorticoids. The European journal of neuroscience, 18 (7), 1739-43 PMID: 14622208

[4] Maguire, E. (2000). Navigation-related structural change in the hippocampi of taxi drivers Proceedings of the National Academy of Sciences, 97 (8), 4398-4403 DOI: 10.1073/pnas.070039597

[5] Arnold MC, Papanicolaou DA, O’Grady JA, Lotsikas A, Dale JK, Straus SE, & Grafman J (2002). Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome. Psychological medicine, 32 (6), 1075-89 PMID: 12214788

[6] Kozora E, Laudenslager M, Lemieux A, & West SG (2001). Inflammatory and hormonal measures predict neuropsychological functioning in systemic lupus erythematosus and rheumatoid arthritis patients. Journal of the International Neuropsychological Society : JINS, 7 (6), 745-54 PMID: 11575596

[7] Shapira-Lichter I, Beilin B, Ofek K, Bessler H, Gruberger M, Shavit Y, Seror D, Grinevich G, Posner E, Reichenberg A, Soreq H, & Yirmiya R (2008). Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory. Brain, behavior, and immunity, 22 (3), 388-98 PMID: 17959355

[8] Yirmiya R, & Goshen I (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, behavior, and immunity, 25 (2), 181-213 PMID: 20970492

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